Cancer predispositions result from defects in DNA damage responses. This integrated multi-institutional Program Project on the Structural Cell Biology of DNA Repair Machines (SBDR) addresses the challenge of characterizing these critical DNA damage responses at the molecular level. Our SBDR renewal application integrates projects that investigate the structural biology and pathway interactions for DNA damage responses key to genetic integrity. The interconnected SBDR projects are: 1) Nucleotide and base excision repair, 2) Transcription-coupled and replication-associated excision repair;3. Homologous recombination and crosslink repair, and 4) Mismatch repair interactions. Together SBDR projects focus on protein conformations, interactions, and complexes that are keystones for understanding and ultimately controlling DNA damage responses for therapeutic purposes. As a whole, SBDR addresses four unifying hypotheses for DNA damage response proteins: 1) their interactions form super-efficient molecular machines to detect, repair, and signal damage, 2) their interactions are structurally regulated by post-translational modifications (PTMs), conformational switching, and disorder-order transitions induced by protein and DNA binding;3) their dynamic assemblies result from linking weak modular interactions to achieve overall high affinities and binding specificities, and 4) their pathway choices and steps are selectively regulated by composite modular interactions that allow interface mimicry, invasion, and DNA damage specific exchanges. SBDR will test hypotheses and achieve program goals by integrating existing strengths with new technologies and strategic collaborations. The Structural Cell Biology (SCB) Core will leverage the successes of the SIBYLS beamline for visualizing protein assemblies and conformations by coupled solution and crystallographic X-ray diffraction analyses, and will add the complementary method of Scanning Force Microscopy. The Administrative Core will continue to manage the SBDR, monitor progress, and facilitate interaction among all investigators. The combined Project and Core efforts will allow SBDR to effectively bridge from protein interactions to pathways, from repair pathway interactions to damage sensing, signaling, and repair responses, and from damage response interactions to cell fate decisions and phenotypes. The application of SBDR results to both understanding and intervention for cancer will be promoted by active interactions with the UCSF Cancer Center. Overall, SBDR results will be fundamental to informed design of epidemiological studies and provide the next step moving from systems biology toward achieving a molecular-based understanding for cancer risk, prevention and treatment.